{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T03:54:11Z","timestamp":1790913251202,"version":"4.1.0"},"reference-count":23,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100012952","name":"Universit\u00e9 Grenoble Alpes","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012952","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001677","name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001677","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007175","name":"Conseil National de la Recherche Scientifique","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007175","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR\u201021\u2010CE17\u20100007"],"award-info":[{"award-number":["ANR\u201021\u2010CE17\u20100007"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR\u201019\u2010CE17\u20100014"],"award-info":[{"award-number":["ANR\u201019\u2010CE17\u20100014"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Multiple morphological abnormalities of the flagella (MMAF) is a severe form of male infertility characterized by immotile spermatozoa with absent, short, coiled, or irregular flagella. Despite advances in whole\u2010exome sequencing, many cases remain genetically unexplained. Here, we identify a homozygous truncating variant in\n                    <jats:italic>LRGUK<\/jats:italic>\n                    (c.1063C&gt;T; p.Arg355Ter) in an infertile man presenting with a typical MMAF phenotype. The variant, identified by whole\u2010exome sequencing in a cohort of 168\u2009MMAF patients and confirmed by Sanger sequencing, is predicted to result in loss of the C\u2010terminal guanylate kinase\u2010like domain. Immunofluorescence showed absence of LRGUK protein in patient spermatozoa, supporting a loss\u2010of\u2010function effect. Semen analysis revealed impaired motility and complete teratozoospermia. Morphological and ultrastructural analyzes demonstrated severe defects affecting both sperm head and flagellum, including disorganized axonemal architecture and central pair abnormalities. Nuclear analyzes showed increased nuclear size, defective chromatin compaction, and elevated DNA fragmentation. Immunostaining further indicated alterations of central apparatus\u2010associated proteins, supporting a role for LRGUK in C1b projection organization. These findings identify LRGUK as a novel gene involved in male infertility, essential for spermatid morphogenesis and flagellum assembly.\n                  <\/jats:p>","DOI":"10.1111\/cge.70220","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T02:07:02Z","timestamp":1784858822000},"page":"538-548","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Biallelic Truncating Variant in\n                    <scp>\n                      <i>LRGUK<\/i>\n                    <\/scp>\n                    Is Associated With Severe Multiple Morphological Abnormalities of the Sperm Flagella and Sperm Nuclear Defects in Humans"],"prefix":"10.1111","volume":"110","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-7990-2512","authenticated-orcid":false,"given":"Wi\u00e2me","family":"Mokkedem","sequence":"first","affiliation":[{"name":"Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility University of Grenoble Alpes  Grenoble France"},{"name":"CHU Grenoble Alpes UM de G\u00e9n\u00e9tique Chromosomique  Grenoble France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeina","family":"Wehbe","sequence":"additional","affiliation":[{"name":"Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility University of Grenoble Alpes  Grenoble France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne\u2010Laure","family":"Barbotin","sequence":"additional","affiliation":[{"name":"CHU Lille Laboratoire de Biologie de la Reproduction\u2010Spermiologie\u2010CECOS  Lille France"},{"name":"Development and Plasticity of the Neuroendocrine Brain University of Lille  Lille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8548-4961","authenticated-orcid":false,"given":"Ang\u00e8le","family":"Boursier","sequence":"additional","affiliation":[{"name":"CHU Lille Laboratoire de Biologie de la Reproduction\u2010Spermiologie\u2010CECOS  Lille France"},{"name":"Development and Plasticity of the Neuroendocrine Brain University of Lille  Lille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0026-9479","authenticated-orcid":false,"given":"C\u00e9lia","family":"Tebbakh","sequence":"additional","affiliation":[{"name":"Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility University of Grenoble Alpes  Grenoble France"},{"name":"CHU Grenoble Alpes UMGI\u2010DPI  Grenoble France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7667-2853","authenticated-orcid":false,"given":"Nicolas","family":"Thierry\u2010Mieg","sequence":"additional","affiliation":[{"name":"CNRS, University of Grenoble Alpes  Grenoble France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4092-1253","authenticated-orcid":false,"given":"Marie","family":"Bidart","sequence":"additional","affiliation":[{"name":"Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility University of Grenoble Alpes  Grenoble France"},{"name":"UM G\u00e9n\u00e9tique Mol\u00e9culaire: Maladies H\u00e9r\u00e9ditaires et Oncologie University Hospital Grenoble Alpes  Grenoble France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Migliaccio","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine University of Campania L. Vanvitelli  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosanna","family":"Chianese","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine University of Campania L. Vanvitelli  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3753-5901","authenticated-orcid":false,"given":"Christophe","family":"Arnoult","sequence":"additional","affiliation":[{"name":"Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility University of Grenoble Alpes  Grenoble France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raoudha","family":"Zouari","sequence":"additional","affiliation":[{"name":"Polyclinique Les Jasmins Centre d\u2019Aide M\u00e9dicale \u00e0 la Procr\u00e9ation  Tunis Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zine\u2010Eddine","family":"Kherraf","sequence":"additional","affiliation":[{"name":"Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility University of Grenoble Alpes  Grenoble France"},{"name":"CHU Grenoble Alpes UMGI\u2010DPI  Grenoble France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1544-7449","authenticated-orcid":false,"given":"Pierre F.","family":"Ray","sequence":"additional","affiliation":[{"name":"Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility University of Grenoble Alpes  Grenoble France"},{"name":"CHU Grenoble Alpes UMGI\u2010DPI  Grenoble France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7572-9096","authenticated-orcid":false,"given":"Guillaume","family":"Martinez","sequence":"additional","affiliation":[{"name":"Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility University of Grenoble Alpes  Grenoble France"},{"name":"CHU Grenoble Alpes UM de G\u00e9n\u00e9tique Chromosomique  Grenoble France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8873-8098","authenticated-orcid":false,"given":"Charles","family":"Coutton","sequence":"additional","affiliation":[{"name":"Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility University of Grenoble Alpes  Grenoble France"},{"name":"CHU Grenoble Alpes UM de G\u00e9n\u00e9tique Chromosomique  Grenoble France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41585\u2010018\u20100003\u20103"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmv020"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/molehr\/gaaf006"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439\u2010020\u201002113\u2010x"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2022.01.011"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24032559"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.75373"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/deab200"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0959\u2010440x(01)00266\u20104"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.34067\/KID.0000001034"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1005090"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201600909R"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/del130"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1063\/4.0000966"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41422\u2010025\u201001135\u20102"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/and.13718"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rbmo.2009.07.002"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/medicina59071313"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2010.11.006"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.050377"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.03.007"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018\u2010025\u201005583\u20102"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010020\u201069359\u20103"}],"container-title":["Clinical 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